Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease. Its prevalence increases with age, and reaches 1% to 2% of subjects over the age of 50. It is characterized by disabling motor symptoms such as akinesia, muscle rigidity, and tremor at rest. These clinical signs can be accompanied by non-motor disorders such as digestive, urinary, or cognitive disorders.
Motor disorders associated with Parkinson's disease are directly related to the degeneration of dopaminergic neurons in the substantia nigra.
The molecular phenomena underlying this neuronal degeneration have not been fully explained but it is suggested that oxidative stress, mitochondrial dysfunction, and abnormal protein aggregation play a key role in the pathogenesis of the disease. Postmortem histological examination of specimens from patients with Parkinson's disease has nearly systematically revealed the accumulation and aggregation of the alpha-synuclein protein within filamentous eosinophil inclusions—the Lewy bodies (Spillantini et al., PNAS, 1998, 95, 669-6473). These inclusions have mainly been detected in the cytoplasm of dopaminergic neurons of the substantia nigra. Remarkably, the Lewy bodies are observable even in the absence of mutations in the alpha-synuclein gene and are thus considered a key marker of Parkinson's disease. Lewy bodies have also been detected in diseases involving loss of brain dopaminergic neurons, such as Lewy body dementia.
The exact causes of Parkinson's disease remain unknown. Environmental factors—such as exposure to pesticides or heavy metals—have been proposed. In parallel, studies of familial forms of Parkinson's disease have identified several genes that are involved in disease onset. However, Parkinson's disease is sporadic in the vast majority of cases, suggesting a multifactorial etiology involving genetic predisposition and exposure to environmental factors.
There is no treatment that cures Parkinson's disease or significantly slows its progression, especially the neuronal degeneration (Seidl, Front Neurol, 2011, 2, 68). The only treatments currently available are designed to reduce the symptoms associated with this disease, such as tremors.
In this context, the development of cell and animal models remains essential to uncovering the mechanisms involved in Parkinson's disease and to developing cures and/or preventive treatments for this disease. One can refer to Betarbet et al. (Bioassays, 2002, 24, 308-318), Blesa et al. (Journal of Biomedicine and Biotechnology, 2012, Article ID 845618), or Blandini et al. (FEBS Journal, 2012, 279, 1156-1166) for a summary concerning animal models of Parkinson's disease.
These publications show that the modeling of Parkinson's disease generally includes the induction of a dopaminergic lesion in the substantia nigra, either chemically or genetically.
The chemical approach involves inducing certain essential biological characteristics of Parkinson's disease by exposing the animal to a chemical agent. 6-hydroxydopamine (6-OHDA) was the first chemical agent used to mimic Parkinson's disease. This model has many disadvantages, however; in particular, 6-OHDA must be administered intracranially and has acute toxicity. Also, administration of 6-OHDA causes neither the appearance of lesions in all areas of the brain involved in Parkinson's disease nor the formation of Lewy bodies. The 6-OHDA model was supplanted by the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)/MPP+ model, which is presently the best-characterized and most-used model. After administration, MPTP crosses the blood-brain barrier and is metabolized by the monoamine oxidases of the astrocytes in MPP+ (1-methyl-4-phenyl-2,3-dihydropyridinum), an inhibitor of mitochondrial complex I. MPP+ specifically targets the nigrostriatal dopaminergic neurons. In many species, including humans, exposure to MPTP leads to degeneration of the dopaminergic neurons in the substantia nigra and induces some of the symptoms associated with Parkinson's disease. This model has many limitations, however. It is generally very difficult to keep animals that have bilateral lesions induced by MPTP alive without administration of L-dopa or dopamine agonists. Also, this model does not simultaneously reproduce all the motor disorders associated with Parkinson's disease. Although the presence of alpha-synuclein aggregates in the form of inclusions has been reported in some primate species, Lewy body formation has never been observed to date (Blesa et al., supra). Finally, the MPTP/MPP+ model is an “acute” model which does not reproduce the slow progression of Parkinson's disease; this makes it difficult to use it to discover new treatments or to define all the biological mechanisms involved in the onset of Parkinson's disease.
More recently, other chemical models based on an herbicide such as pyridinium, paraquat, or other inhibitors of mitochondrial complex I have been evaluated. These models have limitations similar to those of MPTP, particularly a lack of specificity towards the dopaminergic system.
Genetic models based on extinction, mutation, or overexpression of a gene of interest such as alpha-synuclein or LRRK2 (leucine-rich repeat kinase 2) have also been developed. Although these are interesting tools for analysis, they do not provide a completely accurate reproduction of the disease, especially the appearance of Lewy bodies (Dawson et al., Neuron, 2010, 66(5): 646-61). Furthermore, the presence of a genetic mutation in an animal from birth, and even in early embryogenesis, can involve many processes and induce compensation and adaptation phenomena which are not observable in the adult individual, which limits and complicates any transposition of the results to humans.
None of the chemical or genetic models developed so far are capable of reproducing all the symptoms and main markers of Parkinson's disease, especially its progressive development and the appearance of Lewy bodies.
Therefore, there is currently a need for animal and cell models of Parkinson's disease that provide alternatives to those described in the prior art.